BDI Pharma - Inhibitors and Hemophilia.

Inhibitors - What You Should Know

In Hemophilia A and B patients being treated with anti-hemophilic factor products, the development of inhibitors is an ongoing concern. Inhibitors are the result of an immune response to the introduction of foreign factor proteins. Mistaking the factor proteins as infectious, the immune system destroys the proteins needed to treat a bleed, resulting in the infusion being ineffective, the bleeding continuing, and the factor being wasted. Inhibitors cannot be prevented and may occur at anytime. The treatment of an inhibitor is costly, time consuming, and demanding.

Individuals with Hemophilia A develop inhibitors more often than those with Hemophilia B, though the reasons why are unclear.

For those with...	This percent of the population will develop an inhibitor:
Severe Hemophilia A	Up to 25%
Severe Hemophilia B	1.5 - 5%
Mild or Moderate Hemophilia	1-2%

People who have a family history of inhibitors, patients with certain genetic mutations, and minorities with hemophilia are statistically at a higher risk to develop inhibitors. Children under the age of 5 are also at an increased risk. Most inhibitors occur within 5 to 50 days of treatment with factor.

The titer level of an inhibitor is measured in Bethesda Units (BU).

Inhibitor Titer	People with this level are called . . .
0.5 to 5 BU	Low Responders
5+ BU	High Responders

Inhibitor patients fall into three categories:

Patients with inhibitors which are transient and disappear without treatment,
Patients with inhibitors which disappear with immune tolerance induction,
And, patients with inhibitors which are persistent and high-titer.

Transient inhibitors may be fairly common but infrequently diagnosed because they do not noticeably affect the efficacy of treatment.

Although a blood test for inhibitors is usually performed annually by the Hemophilia Treatment Center, one should also be performed if factor replacement is ineffective or prior to surgery.

Treatment

The goal of treatment for a hemophilia patient with an inhibitor is two-fold: to control the bleeding episode and to eliminate the inhibitor. The approach to treatment is dependent upon the titer level of the inhibitor, how the inhibitor level responds to an infusion, and the severity of the bleed

Controlling Bleeding Episodes

ypassing agents are commonly used to stop a bleeding episode in inhibitor patients. The body uses two molecular pathways to promote coagulation, called the intrinsic and extrinsic pathways. The intrinsic pathway utilizes factors VIII and IX (among others). The extrinsic pathway can be strengthened to compensate for the deficiencies of the intrinsic pathway found in Hemophilia A or B by administering a bypassing agent. Two products are available in the US for this purpose:

NovoSeven recombinant FVIIa
Feiba VH anti-inhibitor coagulant complex

These products differ in the required dosage level and interval as well as the method of viral purification used in their preparation. To compare these products, see our product comparison chart here. Course of treatment must be determined on an individual basis.

A low responder whose inhibitor level doesnt rise above 5 BU in response to an infusion of a factor concentrate may require a larger dose of factor in order to overwhelm the inhibitor. Dosage must be closely clinically monitored.

In a high responder whose inhibitor level rises above 5 BU only in response to an infusion of factor concentrate, the effectiveness of factor products in treating a bleed is greatly reduced. Factor is usually administered to these patients in the event of a severe bleed that is life or limb threatening. Bypassing agents such as NovoSeven and Feiba VH are commonly used in the treatment of bleeding episodes in these patients.

In the treatment of a high responder whose inhibitor level is consistently above 5 BU even without exposure to a factor product, the use of factor concentrates is largely ineffective and may promote an anamnestic response, resulting in an increased inhibitor level. NovoSeven or FEIBA are available options used to control bleeding episodes in these patients.

Elimination of Inhibitors

Some inhibitors are transient and disappear without treatment. In patients with persistent inhibitors, a course of treatment called Immune Tolerance Induction is common. Immune Tolerance Induction involves overwhelming the immune system through administering a high dosage of factor on a regular basis, usually at least several days per week. The course of treatment may span several years, making it time consuming and costly.

The effectiveness of Immune Tolerance Induction is determined by many factors. It is most effective in patients with a lower titer of inhibitors who do not

miss any treatments. Repeated attempts at Immune Tolerance Induction often produce less successful results each subsequent attempt. Patients who begin with much higher titers have a lower success rate with Immune Tolerance Induction. Certain genetic mutations can also reduce its success.

For Further Information

To learn more about inhibitors, visit either of the following on the web:

National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/)
National Hemophilia Foundation (http://www.hemophilia.org/)

References

Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 1999; 5: 145-154.

Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004; 2: 899-909.

Lacroix, R.N., Sylvie, Nora Schwetz, R.N., Andrea Pritchard, R.N., Kathy Mulder, B.P.T., and Nichan Zourikian, B.P.T. All About Inhibitors. 1999, Canadian Hemophilia Society.